We preliminarily exploring the possibility of DNA methylation as a mechanism through which epigenetic signals are passed from mother to offspring using a MeDIP-chip assay on the Affymetrix Human Tiling 2.0R Array. DNA methylation in peripheral blood leukocytes was compared between 14 non-diabetic offspring of diabetic mothers and 14 non-diabetic offspring of nondiabetic mothers. Data were analyzed using the model based analysis of tiling arrays (MAT) algorithm implemented in the Partek Genomic Suite. Differentially methylated promoters (N=5,975) were subjected to KEGG pathway analysis and the top pathway results were Type II Diabetes (p<0.003) and maturity onset diabetes of the young (MODY) (p<0.005). These preliminary findings support the hypothesis that epigenetic dysregulation of genes known to be involved in pancreatic development and insulin secretion mediate the increased risk for diabetes in offspring of diabetic mothers. Recent advances in genomic techniques now allows for epigenotyping of 450,000 individual CpG sites using the Illumina Infinium Methylation Array.Peripheral blood leukocytes from 420 non-diabetic Pima Indians were epigenotyped using the Illumina Infinium Methylation Array. Subjects were selected as being either the offspring of a T2D mother (mother had documented hyperglycemia at an exam during the 9 months preceding the child's birth) or the offspring of a non-T2D mother (mother had documented normoglycemia during the 9 months prior to the child's birth and had a non-diabetic exam >1 year after the childs birth). Data from 423,343 CpG sites in 388 individuals (N= 187 with exposure and 201 without exposure to intrauterine diabetes) passed all quality control measures. A Logistic Regression model with appropriate adjustments was used to estimate the association between exposure and methylation status. Thirty-nine differentially methylated genes achieved epigenome-wide significance after correction for false discovery rate (FDR). A Cox Proportional Hazard model in individuals with follow-up data on diabetes status determined that an intergenic CpG site (maps between FLJ42875 and PRDM16) significantly increased T2D risk (P value = 9.7E-5). This study is the first to identify differentially methylated genes in response to intrauterine diabetes exposure at the epigenome-wide significance. Detailed studies of the biologic pathways affected by these differentially methylated genes are ongoing, which will lead to knowledge of the metabolic changes that underlie the epidemiologic observation that maternal diabetes affects diabetes risk in offspring.